Field effect transistor-based bio-sensor

ABSTRACT

An apparatus comprises: a sensing element formed on a buried oxide layer of a substrate and providing communication between a source region and a drain region; a gate dielectric layer on the sensing element, the gate dielectric layer defining a sensing surface on the sensing element; a passive surface surrounding the sensing surface; and a compound bound to the sensing surface and not bound to the passive surface, the compound having a ligand specifically configured to preferentially bind a target molecule to be sensed. An electrolyte solution in contact with the sensing surface and the passive surface forms a top gate of the apparatus.

CROSS REFERENCE

This application is a continuation of and claims priority to copendingU.S. patent application Ser. No. 13/965,346, filed on Aug. 13, 2013,which is a continuation of and claims priority to copending U.S. patentapplication Ser. No. 13/723,514, filed on Dec. 21, 2012, the contents ofboth applications being incorporated herein by reference in theirentireties.

BACKGROUND

The exemplary embodiments of this invention relate generally tobio-sensors and, more particularly, to bio-sensors based on field effecttransistors.

Sensors based on field effect transistors (FETs) can be used in avariety of different bio-sensing applications to detect variousbiomolecules. In such sensors, a sensing surface is modified with afunctional group that acts as a receptor to bind a target species havinga charge. The target species may be any biomolecule such as a protein,virus, drug moeity, or the like. The charge of the bound target specieson the sensing surface causes change in the drain current that can beused in a bio-sensing application.

The sensitivity of a FET-based bio-sensor is generally limited due tothe probability of an unbound target species attaching to the sensingsurface. In the case of typical sensors, both sensing and non-sensing(also known as passive) surfaces are of the same material (i.e. SiO₂)and therefore have the same chemistry. Hence, an unbound target speciesin a solution can bind to both sensing and passive surfaces. Thesensitivity depends on the ratio A_(sense)/A_(passive) where A_(sense)is the sensing surface area and A_(passive) is the passive surface area.Since the passive surface area is significantly larger than the sensingsurface area (e.g., generally on the order of 10³ to 10⁴ times as large)and since the surfaces are of the same chemistry, the majority of targetspecies would attach to the passive surface and not to the sensingsurface. Based on the construction of bio-sensors of this type, aparticular molecule of a target species in dilute concentrations may notbe detected due to the low probability of such a molecule binding to thesensing surface, thereby providing inaccurate detection readings.Consequently, having sensing and passive surfaces of disparate surfaceareas and of the same material limits the sensitivity of a FET-basedbio-sensor.

BRIEF SUMMARY

In one exemplary aspect, an apparatus comprises: a sensing elementformed on a buried oxide layer of a substrate and providingcommunication between a source region and a drain region; a gatedielectric layer on the sensing element, the gate dielectric layerdefining a sensing surface on the sensing element; a passive surfacesurrounding the sensing surface; and a compound bound to the sensingsurface and not bound to the passive surface, the compound having aligand specifically configured to preferentially bind a target moleculeto be sensed. An electrolyte solution in contact with the sensingsurface and the passive surface forms a top gate of the apparatus.

In another exemplary aspect, an SOI finFET-based sensor comprises: asensing element formed on a substrate having a source region and a drainregion, the sensing element comprising a silicon member extendingbetween the source region and the drain region; a gate dielectric layerformed over the sensing element, the gate dielectric layer comprising asensing surface over the sensing element; a passive surface surrounding,adjacent to, or around the sensing surface, a material of the passivesurface being dissimilar to a material of the sensing surface; and ahydroxamic acid bound to the sensing surface, the hydroxamic acid havinga ligand specifically configured to bind a target molecule to be sensed.The SOI finFET-based sensors are exemplary, as the embodiments describedherein are applicable to all other types of FET sensors such as bulkFETs, planar FETs, and the like.

In another exemplary aspect, a method of forming a sensor comprises:disposing a silicon sensing element on a substrate; depositing a gatedielectric layer on the silicon sensing element, the gate dielectriclayer forming a sensing surface on the silicon sensing element;depositing a passive surface on the substrate surrounding, adjacent to,or around the sensing surface, a material of the passive surface beingdifferent from a material of the sensing surface; and modifying thesensing surface with a compound to receive a target species.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The foregoing and other aspects of exemplary embodiments are made moreevident in the following Detailed Description, when read in conjunctionwith the attached Drawing Figures, wherein:

FIG. 1 is a side view of a FET-based sensor;

FIG. 2 is a side view of a FET-based sensor having sensing surface areasand passive surface areas comprising different materials;

FIG. 3 is a top view of the sensor of FIG. 2;

FIG. 4 is a schematic representation of an exemplary process ofassembling biotin hydroxamic acid over a sensing surface area of theFET-based sensor of FIG. 2;

FIG. 5 is a schematic representation of an exemplary process of usingthe assembled biotin hydroxamic acid of FIG. 4 to detect streptavidin asthe target protein;

FIG. 6A is a scanning electron microscopic image of a target protein ona sensing surface area on the FET-based sensor of FIG. 2;

FIG. 6B is a graphical representation showing a relationship betweencapacitance and gate bias voltage for systems on FET-based biosensors;

FIG. 7A is a graphical representation indicating the self-assembly ofoctadecane hydroxamic acid on hafnium dioxide; and

FIG. 7B is a graphical representation illustrating a lack ofself-assembly of octadecane hydroxamic acid on silicon dioxide.

DETAILED DESCRIPTION

Exemplary embodiments of a FET-based sensor fabricated on asilicon-on-insulator (SOI) substrate and methods related to thefabrication thereof are disclosed herein. The SOI FET-based sensorcomprises lightly-doped fin-shaped silicon forming a channel, heavilydoped source and drain regions, and a gate dielectric layer covering thethree sides of the silicon fin. The gate dielectric surface is a sensingsurface, and detection occurs when target molecules bind to the gatedielectric surface. All surfaces other than the gate dielectric arereferred as passive surfaces because no detection occurs when targetmolecules bind to them. The gate dielectric layer comprises a firstmaterial (e.g., HfO₂) that is different from that of the passivesurfaces, which comprises a second material (e.g., SiO₂). An electrolytesolution in contact with the sensing and passive surfaces forms a topgate of the apparatus. Since the FET-based sensor is fabricated on SOIsubstrate, it has a buried oxide layer on the substrate. The substrateforms the back gate.

Since the sensing and passive surfaces are of different materials withdifferent surface chemistries, this difference provides a means toselectively modify the sensing surface by using a self-assembly methodsuch that the target molecules preferentially bind to the sensingsurface. To achieve this selective modification, molecules with two keyattributes are used for self-assembly: (i) a molecule preferentiallybinds to the gate dielectric surface in comparison to the passivesurface, and (ii) the molecule has a ligand that preferentially bindsthe target molecule.

As an example, selective modification the HfO₂ sensing surface with SiO₂as the passive surface such that the target protein streptavidin wouldonly bind to the sensing surface is demonstrated as follows: (1)hydroxamic acid compound with biotin as the ligand is used in theself-assembly process; (2) hydroxamic acid preferentially binds to theHfO₂ sensing surfaces in comparison to the SiO₂ passive surfaces, andbiotin preferentially binds to the target protein streptavidin; (3) asolution of biotin hydroxamic acid compound is formed, and the sensingand surrounding passive surfaces are exposed to the solution for severalhours; and (4) during the exposure time, biotin hydroxamic acidmolecules attach themselves preferentially to the HfO₂ sensing surface.It may be noted that to detect another type of target protein, thebiotin may be replaced with another molecule which would specificallybind the new target protein.

The SOI fin FET-based sensors are exemplary, as the embodimentsdescribed herein are applicable to all other types of FET sensors suchas bulk FETs, planar FETs, and the like. In any embodiment, the gatedielectric sensing and passive surfaces are of two different materials,and the surface materials are chosen such that selective surfacemodification can occur easily via the self-assembly method. .

As shown in FIG. 1, one exemplary embodiment of a FET-based sensor foruse as a bio-sensor is designated generally by the reference number 100and is hereinafter referred to as “sensor 100.” Sensor 100 comprises asubstrate 120, a buried oxide layer 110 formed on the substrate 120, asensing element 150 disposed on the buried oxide layer 110 between asource region 130 and a drain region 140, and a gate dielectric layer160 deposited on the sensing element 150 and the source region 130 anddrain region 140. The gate dielectric layer 160 comprises a dielectriclayer 162 and a layer of metal oxide 165, which may be arranged as twodistinct layers or as a single layer. An exposed surface of the metaloxide 165 defines a sensing surface 170. A solution 175 in contact withthe sensing surface 170 forms a top gate of the sensor 100.

The buried oxide layer 110 may comprise silicon dioxide (SiO₂) or thelike. Materials from which the substrate 120 may be formed include, butare not limited to, silicon-on-insulator (SOI), bulk substrate, siliconcarbide, silicon alloys, germanium, germanium alloys, gallium arsenide,and the like. When the substrate 120 comprises SOI, the substrate 120forms a back gate on the sensor 100. When the substrate 120 comprisesbulk substrate, however, the sensor 100 will only have the top gatecomprising the solution.

The sensing element 150 may be a fin or other structure comprising achannel of undoped silicon (e.g., a silicon nanowire). The dielectriclayer 162 of the gate dielectric layer 160 may comprise SiO₂ or thelike. The metal oxide 165 of the gate dielectric layer 160 may compriseany suitable metal oxide such as hafnium dioxide (HfO₂) or the like.

As shown in FIG. 2, sensors 100 are arranged such that sensing elements150 are positioned adjacent to (and may be surrounded by) passivesurfaces 180 to define sensing areas (A_(sense)) and passive areas(A_(passive)). The passive surfaces 180 comprise SiO₂. As shown, thesensing element 150 with the gate dielectric layer 160 thereon mayextend above the passive surface 180 by a height h to define the sensingelements 150 of the sensors 100 as fins having sidewalls and topsurfaces. In other embodiments, the sensing element 150 may be planarwith the passive surface 180.

As shown in FIG. 3, the sensing element 150 (hereinafter “fin 150”) canextend between the source region 130 and the drain region 140, which aredefined on the buried oxide layer 110 of the sensor 100 proximateopposing ends of the fin 150. Both the source region 130 and the drainregion 140 comprise heavily doped n+ or p+ silicon. A layer of SiO₂covers both the source region 130 and the drain region 140.

Referring to both FIGS. 2 and 3, the sensing surface 170 comprisesantibodies self-assembled and bound to the metal oxide 165 of the gatedielectric layer 160. The antibodies are selected so as topreferentially bind to the metal oxide 165 and not to the material ofthe passive surface 180 (e.g., SiO₂). The antibodies self-assembled onand bound to the metal oxide are also selected so as to bind withspecific biomolecules to be detected.

To detect the biomolecules, a drain current having exponentialdependence on an applied gate voltage is measured. The majority ofbiomolecules are charged. Therefore, when a charged biomolecule is inthe vicinity of a fin 150, the biomolecule causes the drain current tochange. The change in drain current is a measure of the sensitivity ofthe sensor 100.

When the sensor 100 is immersed in the solution 175 (e.g., anelectrolyte solution as shown in FIG. 1) that includes the biomoleculesto be detected, the solution 175 in contact with the fin(s) 150 formsthe top gate. The gate voltage is applied to the solution using a metalelectrode (e.g., AgCl/Ag) immersed in the solution 175. In someembodiments, a positive polarity voltage is applied at the drain region140, source voltage is held at zero, and a voltage is applied at themetal electrode, thereby causing the drain current to flow between thesource region 130 and the drain region 140. When biomolecules attach tothe sensing surface 170, the drain current changes, thereby allowing forthe detection of the biomolecules.

In the exemplary embodiment of the present invention as shown in FIGS. 2and 3, the likelihood of molecules of a target species in a diluteconcentration not being detected due to the low probability of such amolecule binding to a surface area in a sensor is overcome or at leastmitigated by providing the sensing surfaces 170 and passive surfaces 180of the sensor 100 as dissimilar materials.

To illustrate the enhanced sensitivity of the sensor 100 (as compared tosensors in which the sensing surfaces and passive surfaces are the samematerial), the material of the sensing surface 170 hereinafter comprisesthe HfO₂, and the material of the passive surface 180 hereinaftercomprises the SiO₂. Since the sensing surface 170 and the passivesurface 180 comprise dissimilar materials, the chemistry of the sensingsurface 170 can be selectively modified so that specific molecules orspecies can be targeted for binding to the sensing surface 170 withoutbinding to the passive surface 180. With HfO₂ as the material of themetal oxide layer 165, the sensing surface 170 is compatible with gatedielectric layers in recent generation CMOS (complementary metal oxidesemiconductor) devices. Furthermore, HfO₂ is compatible with currentsilicon technology in general.

In embodiments in which the metal oxide layer 165 is HfO₂ and thepassive surface 180 is SiO₂, the sensing surface 170 can be modifiedsuch that a biomolecule of a target species is a particular protein thatbinds to the HfO₂ and not to the surrounding SiO₂ of the passive surface180. After assembling the structure of the FET for the sensor 100, thismodification of the sensing surface 170 comprises (i) the synthesis of amolecule that would attach to HfO₂ on one end and to the desired proteinat the other end and (ii) self-assembly of the synthesized molecule onthe metal oxide layer 165. As used herein, the term “self-assembly”refers to the ability of a molecule to autonomously attach to a surface.

One example of the modification of the sensing surface 170 employsattaching a hydroxamic acid on the HfO₂ of the metal oxide layer 165 toeffect the synthesis and self-assembly process. A suitable hydroxamicacid can be formed by any suitable reaction mechanism (e.g., from analdehyde in basic solution containing a sulfonamide, or by any method ofcoupling a hydroxylamine to a carboxylic acid). One exemplary hydroxamicacid is shown below:

The attachment of the hydroxamic acid to the HfO₂ of the sensing surface170 (and not to the surrounding SiO₂ surface) on one end is effected byreleasing the hydrogen atom from the —OH group and allowing theresulting negatively charged oxygen atom to bond to the hafnium, therebycausing the hydroxamic acid to form a film on the hafnium oxide layer ina self-assembling process. The described embodiments are not limited tothe use of hydroxamic acids, however, as other acids (e.g., phosphonicacids) may be employed depending on the particular metal oxide of themetal oxide layer 165 and the desired biomolecule to be detected.

In the hydroxamic acid as shown above, R can be any hydrocarbon chain,ring, or similar ligand usable as a building block capable of givingspecificity to a target molecule (e.g., a protein). In particular, Rcould be any antibody having an attribute suitable for binding aspecific target protein. For example, the antibody could be selected soas to preferentially bind prostate specific antigen (PSA).

As shown in FIG. 4, one example of a system in which the R in thehydroxamic acid is biotin is described. Biotin is a crystalline,water-soluble vitamin (also known as Vitamin H, Vitamin B7, and CoenzymeR) having the formula C₁₀H₁₆O₃N₂S that is present in small amounts inall living cells.

To build the biotin system as an example for use in the sensor 100,biotin hydroxamic acid 300 is synthesized and subsequentlyself-assembled as a film on the HfO₂ of the metal oxide layer 165 toform the sensing surface 170. The structure of the biotin hydroxamicacid 300 is shown below:

The biotin hydroxamic acid 300 is self-assembled over the HfO₂ of themetal oxide layer 165 to form the sensing surface 170 by removing thehydrogen atom from the —OH group and allowing the negatively chargedoxygen atom to bond to the HfO₂, thereby forming a film of the biotinhydroxamic acid on the HfO₂.

As shown in FIG. 5, the exposure of the sensing surface 170 comprisingthe biotin hydroxamic acid 300 synthesized and self-assembled as thefilm on the HfO₂ allows for the detection of streptavidin 310 (as thetarget protein) in an aqueous solution. Streptavidin is a tetramericprotein that is isolated from the bacterium Streptomyces avidinii andhas a high affinity for biotin. In such a system, the streptavidin 310bonds to the biotin hydroxamic acid 300 to form a strong noncovalentbiological bond.

As shown in FIGS. 6A and 6B, the streptavidin 310 is bound to the biotinportion of the biotin hydroxamic acid 300 coupled to the HfO₂. In FIG.6A, gold nanoparticles coated with streptavidin are exposed to the HfO₂surface, which has undergone the self-assembly step for biotinhydroxamic acid. Streptavidin binds to the HfO₂ surface, therebyindicating that the HfO₂ surface is coated with biotin. As a result, thescanning electron micrograph (SEM) image shows that streptavidin-coatednanoparticles bound to the HfO₂ surface, and that self-assembly of thebiotin hydroxamic acid 300 occurs as a monolayer on the HfO₂ of thesensing surface 170. A similar experiment was carried out with regard tothe SiO₂ of the passive surface 180. However, an analogous self-assemblyof the biotin hydroxamic acid 300 is not observed for the SiO₂ of thepassive surface 180.

In FIG. 6B, capacitance-voltage (C-V) is measured for the HfO₂ coveredwith the biotin hydroxamic acid 300 before and after exposure of thesensing surface 170 to the streptavidin 310. A flatband voltage for theC-V curve shifts when the biotin-coated HfO₂ surface is exposed tostreptavidin protein in solution. The change in the flatband voltageimplies that the streptavidin is binding to the biotin-coated HfO₂surface. Such a change in flatband voltage causes the drain current (thesensing current) in the sensor 100 to vary. Analogous shifting on theSiO₂ of the passive surface 180 does not occur.

Similar schemes using other hydroxamic acids in which R is a differentligand can be carried out for other target species. For example, metaloxides other than the HfO₂ can be disposed on the sensing surface 170,and such metal oxides may be coated with hydroxamic acids in which the Ris an antibody that would bind a targeted protein such as PSA. The R maybe any other ligand capable of binding other target species including,but are not limited to, DNA, RNA, and the like.

By way of an additional example of the modification of the sensingsurface 170, a self-assembly process can utilize octadecane hydroxamicacid (ODHA) on the HfO₂ of the sensing surface 170. The ODHA is ahydroxamic acid (as shown above) in which R is CH₃(CH₂)₁₆.

The assembly of the ODHA on the HfO₂ can be studied using, for example,a water droplet contact angle measurement technique. In such atechnique, because the ODHA is hydrophobic, the expected contact anglefor self-assembly of ODHA on the HfO₂ is greater than 90 degrees. Asshown in FIG. 7A, the contact angle of the ODHA on the HfO₂ isdetermined to be about 110 degrees, accordingly indicating theself-assembly of ODHA on the HfO₂. In contrast, as shown in FIG. 7B, thecontact angle of the ODHA on the SiO₂ is determined to be about 40degrees, which indicates the lack of self-assembly of ODHA on the SiO₂.Although the self-assembly of the ODHA on HfO₂ is described toillustrate the synthesis of the ODHA on the HfO₂ and not on the SiO₂,the ODHA assembled on the HfO₂ may function as a receptor for a suitabletarget species.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a,” “an,” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be further understood that the terms “comprises”and/or “comprising,” when used in this specification, specify thepresence of stated features, integers, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, integers, steps, operations, elements,components, and/or groups thereof.

The description of the present invention has been presented for purposesof illustration and description, but is not intended to be exhaustive orlimited to the invention in the form disclosed. Many modifications andvariations will be apparent to those of ordinary skill in the artwithout departing from the scope and spirit of the invention. Theembodiments were chosen and described in order to best explain theprinciples of the invention and the practical applications, and toenable others of ordinary skill in the art to understand the inventionfor various embodiments with various modifications as are suited to theparticular uses contemplated.

1. An apparatus, comprising: a buried oxide layer formed on a substrate; a sensing element comprising silicon nanowire formed on the buried oxide layer and forming a channel for providing a current flow between a source region and a drain region, each of the source region and the drain region comprising heavily doped silicon; a sensing surface on the sensing element, the sensing surface comprising a dielectric layer and a metal oxide on the sensing element; a passive surface over the buried oxide layer and adjacent to the sensing surface, the passive surface being of a material that is dissimilar to a material of the sensing surface; and a compound bound to the sensing surface on the sensing element and not bound to the passive surface, the compound having a ligand specifically configured to preferentially bind a target biomolecule to be sensed on the sensing element where the binding of the target biomolecule is capable of causing a change in the current flow between the source region and the drain region to sense the target biomolecule on the sensing surface.
 2. The apparatus of claim 1, wherein the passive surface comprises a dielectric material to which the compound is not bound.
 3. The apparatus of claim 1, wherein the silicon nanowire is undoped.
 4. The apparatus of claim 1, wherein the silicon nanowire is lightly doped.
 5. The apparatus of claim 1, wherein the dielectric layer and the metal oxide of the sensing surface are arranged as separate distinct layers.
 6. The apparatus of claim 1, wherein the source region and the drain region are covered by a layer of SiO₂.
 7. The apparatus of claim 1, wherein the metal oxide of the sensing surface comprises HfO₂, the compound comprises either a hydroxamic acid or a phosphonic acid bound to the HfO₂, and the passive surface comprises SiO₂.
 8. The apparatus of claim 7, wherein the hydroxamic acid or the phosphonic acid binds to the HfO₂ by self-assembly on the HfO₂ but not on the SiO₂.
 9. The apparatus of claim 1, wherein the sensing surface comprises HfO₂, the compound comprises hydroxamic acid bound to the HfO₂, and the hydroxamic acid includes the ligand specifically configured to bind the target biomolecule.
 10. The apparatus of claim 9, wherein the ligand is biotin.
 11. The apparatus of claim 10, wherein the biotin and the hydroxamic acid form biotin hydroxamic acid that binds streptavidin protein as the target biomolecule.
 12. An apparatus, comprising: a buried oxide layer formed on a substrate; a silicon nanowire disposed on the buried oxide layer and forming a channel for providing a current flow between a source region and a drain region, each of the source region and the drain region comprising doped silicon; a sensing surface on the silicon nanowire, the sensing surface comprising a dielectric layer and a metal oxide; a passive surface over the buried oxide layer and adjacent to the sensing surface, the passive surface being of a material that is dissimilar to a material of the sensing surface; and a compound bound to the sensing surface and not bound to the passive surface, the compound having a ligand specifically configured to preferentially bind a target biomolecule to be sensed on the silicon nanowire where the binding of the target biomolecule is capable of causing a change in the current flow between the source region and the drain region to sense the target biomolecule on the sensing surface.
 13. The apparatus of claim 12, wherein the passive surface comprises a dielectric material to which the compound is not bound.
 14. The apparatus of claim 12, wherein the silicon nanowire is undoped.
 15. The apparatus of claim 12, wherein the silicon nanowire is lightly doped.
 16. The apparatus of claim 12, wherein the dielectric layer and the metal oxide of the sensing surface are arranged as separate distinct layers.
 17. The apparatus of claim 12, wherein the source region and the drain region are covered by a layer of SiO₂.
 18. The apparatus of claim 12, wherein the metal oxide of the sensing surface comprises HfO₂, the compound comprises either a hydroxamic acid or a phosphonic acid bound to the HfO₂, and the passive surface comprises SiO₂.
 19. The apparatus of claim 18, wherein the hydroxamic acid or the phosphonic acid binds to the HfO₂ by self-assembly on the HfO₂ but not on the SiO₂.
 20. The apparatus of claim 12, wherein the sensing surface comprises HfO₂, the compound comprises hydroxamic acid bound to the HfO₂, and the hydroxamic acid includes the ligand specifically configured to bind the target biomolecule. 